Is DNMT3B p.Ala14Pro (c.40G>C) pathogenic?

DNMT3B p.Ala14Pro (c.40G>C) is classified Uncertain significance in DNMT3B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-21). AlphaMissense: likely benign (0.111); Very rare (popmax 0.00466%, nfe); Associated with immunodeficiency-centromeric instability-facial anomalies syndrome.

What condition is associated with DNMT3B p.Ala14Pro (c.40G>C)?

DNMT3B p.Ala14Pro (c.40G>C) is associated with immunodeficiency-centromeric instability-facial anomalies syndrome (ClinVar).

How common is DNMT3B p.Ala14Pro (c.40G>C) in the general population?

DNMT3B p.Ala14Pro (c.40G>C) is very rare (popmax 0.00466%, nfe) (gnomAD).

What do computational predictors say about DNMT3B p.Ala14Pro (c.40G>C)?

AlphaMissense predicts likely benign (score 0.111) — an in-silico prediction, not a clinical call.

DNMT3B p.Ala14Pro

c.40G>C · rs770859652 · VCV1404403

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.111 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00466%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

immunodeficiency-centromeric instability-facial anomalies syndrome

Computational evidence

Protein change
AlphaMissense	0.111	likely benign
REVEL	0.326	indeterminate
SaProt	LLR -6.81	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	GERP -0.51, phastCons 0.92
Regional constraint	o/e 0.94	unconstrained · MANE · 8,530 bp · p 0.27 · regional, not allelic
Overall
CADD	21.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00466% European (non-Finnish) · 55/1,180,026 alleles

Filtering AF 0.00367% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00329%

Overall 0.00347% 56/1,613,884 alleles · very rare exomes 47/1,461,774 · genomes 9/152,110 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00466%	21,455
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: DNMT3B
Protein: p.Ala14Pro
Coding: c.40G>C
MANE Select: NM_006892
dbSNP: rs770859652
Type: single nucleotide variant
Location: chr20:32780363 (GRCh38)
Gene constraint: LOEUF 0.396 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 73.18 · 47 PDB
Residue 14: the 'interaction with dnmt1 and dnmt3a' region; the 'disordered' region

Full DNMT3B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

immunodeficiency-centromeric instability-facial anomalies syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DNMT3B p.Ala14= Benign/Likely benign ★★ same residue
DNMT3B c.2421-11G>A Pathogenic/Likely pathogenic ★★ same condition
DNMT3B p.Ala603Thr Pathogenic/Likely pathogenic ★★ same condition
DNMT3B p.Arg826Cys Pathogenic/Likely pathogenic ★★ same condition
DNMT3B p.Arg840Gln Likely pathogenic ★★ same condition
DNMT3B p.Asp653Asn Pathogenic/Likely pathogenic ★★ same condition
DNMT3B p.His814Arg Likely pathogenic ★★ ⚠ same condition
DNMT3B p.Val613Ala Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/dnmt3b-p-ala14pro (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown